The elucidation of the molecular defects in patients with dyslipoproteinemias provides the unique opportunity to acquire new information on lipoprotein metabolism in normal subjects as well as patients with specific dyslipoproteinemias. Knowledge of the precise genetic disease in dyslipoproteinemic patients enables more effective approaches to screening potential affected individuals and establishing diagnosis in patients at an early age permitting treatment to be initiated during the initial course of the disease. The present studies identified the molecular defect in a kindred with hereditary systemic amyloidosis A mutant form of apoA-I, designated apoA-I(Iowa), contained a single amino acid substitution of a glycine->arginine at residue 26 and was the molecular defect in this family. The mutant A-I apolipoprotein was catabolized at a rapid rate leading to low levels of plasma HDL. In addition, the mutation resulted in a change in the molecular properties of the apolipoprotein leading to its accumulation in tissues. The accumulation of the mutant apolipoprotein was responsible for the amyloid accumulation in the disease. A severe form of type III hyperlipoproteinemia was identified in a young female, and was shown to be due to a mutant apoE designated apoE-4(Phil.). ApoE-4(Philadelphia) had two separate mutation, arginine->cysteine at residue 145 and lysine to glutamic acid at amino acid 13. Kinetic studies established that the mutant apoE-4(Phil.) was responsible for the hyperlipidemia.